Acetylcholinesterase Inhibitors Research Articles

Neuroprotective Effects of Curcumin against Chronic Chlorpyrifos- Induced Oxidative Damage in Rat Brain Tissue.

Chlorpyrifos (CPF) is an organophosphate pesticide that inhibits acetylcholinesterase (AChE) activity. Investigations have also focused on its neurotoxicity, which is independent of AChE inhibition. Here, we evaluated the effect of CPF on oxidative indices in the brain tissue and explored the protective effect of curcumin (Cur) against its toxicity. Forty male Wistar rats were divided into five groups, each consisting of eight rats (n = 8) per group. Animals were administrated by oral gavage for 90 days with the following treatments: control (C), CPF, CPF + CUR 25 mg/kg, CPF + CUR50, and CPF + cur 100 received olive oil, CPF, CPF plus 25 mg/kg of CUR, CPF plus 50 mg/kg of CUR, and CPF plus 100 mg/kg of CUR, respectively. After anesthetization, animal brain tissues were obtained for assessment of oxidative stress indices. The concentration of MDA significantly increased in the brains of the CPF group as compared to the control group (p < 0.01). Also, a significant decrease in MDA concentrations was observed in the brains of rats in the CPF + Cur 100 group compared to the CPF group (p < 0.05). A significant decrease was noted in the GSH concentration in the brains of the CPF group compared to the control group (p < 0.05). Treatment with Cur at 100 mg/kg exhibited a significant increase in GSH concentrations in the brains of the CPF-exposed group compared to the CPF group without Cur administration (p < 0.05). The concentration of NO exhibited a significant increase in the brains of the CPF group when compared to the control group (p < 0.05). Also, a significant decrease in NO concentration was observed in the brain tissue of the CPF + Cur 100 group compared to the CPF group (p < 0.05). Our data establish that chronic exposure to CPF induced oxidative stress in brain tissue, which was reversed by CUR administration. Additional experimental and clinical investigations are needed to validate the efficacy of CUR as a potential antidote for CPF poisoning.

Efficient Access to New Thienobenzo-1,2,3-Triazolium Salts as Preferred Dual Cholinesterase Inhibitors.

In previous research, 1,2,3-triazolium salts showed significant biological activity as potential inhibitors of cholinesterase enzymes (ChEs), which are crucial for neurotransmission. In this research, pairs of uncharged thienobenzo-triazoles and their charged salts were prepared in order to further examine the role of the positive charge on the nitrogen of the triazole ring in interactions within the active site of the enzymes, and to compare the selectivity of 1,2,3-triazolium salts in relation to their uncharged analogs obtained by photochemical cyclization. Neutral thienobenzo-triazoles showed very good selective activity toward butyrylcholinesterase (BChE), while their salts showed excellent non-selective inhibition toward both BChE (the most active 23: IC50 0.47 μM) and acetylcholinesterase (AChE) enzymes (the most active 23: IC50 4.4 μM). These new structures with incorporated 1,2,3-triazolium salts present the new scaffold for drug development as it is known that the current therapy in Alzheimer's disease (AD) comprises selective AChE inhibitors, while in Parkinson's and all stages of AD, non-selective inhibitors of ChEs are preferred. Molecular docking of the selected compounds and their corresponding salts into the active sites of ChEs was conducted to identify the interactions responsible for the stability of the non-covalent cholinesterase-ligand complexes. As genotoxicity studies are crucial when developing new active substances and finished drug forms, in silico studies for all the synthesized compounds have shown that compound 18 is the most promising candidate for genotoxic safety.

Study the effect of Convolvulus pilosellifolius Desr. as antialzheimer and identification of its active compounds

The phenolic pattern of the plant using chromatographic and spectroscopic methods. Three flavonoid and two phenolic compounds were isolated for first time from the alcoholic plant extract which identified as; Quercetin-3’-galactoside, Quercetin-7-glucoside, Quercetin −3-glucoside and two phenolic compounds identified as Methyl-trans-dihydroxy cinnamic acid and Methyl-cis-dihydroxy cinnamic acid, they were isolated and purified using classical and modern chromatographic methods; (PC, TLC, CC and HPLC); identified by Rf, UV,1H NMR,13C NMR and 2D NMR (HMQC) spectroscopy. The activity of total alcoholic extract of Convolvulus pilosellifolius as antialzheimer was investigated concerning its activity as acetylcholine esterase inhibitor. The recorded IC50 was 0.391 and 0.131 µg/mL for the extract and donepezil respectively. The activity of isolated compounds as acetylcholine esterase inhibitor were evaluated by Autodock Vina software to perform the docking protocol. This revealed that the most active compound was Quercetin-3Ì· galactoside.

Pharmacology and toxicology of Acetylcholinesterase: mechanisms, therapeutic potential, and environmental impact

Acetylcholinesterase (AChE) is a critical enzyme in the nervous system, responsible for terminating synaptic transmission by hydrolyzing acetylcholine. Due to its key role in neurotransmission, AChE and its inhibitors have become significant in treating neurological disorders such as Alzheimer’s, Parkinson’s, and Myasthenia Gravis. However, AChE inhibitors are also widely used in agriculture, posing potential environmental hazards as pesticides. This review provides a detailed analysis of the pharmacological role, therapeutic applications, and toxicological implications of AChE inhibitors. While these compounds offer therapeutic benefits, their environmental persistence and non-target toxicity raise ecological concerns. Balancing the dual impact of AChE inhibitors is vital to maximizing their benefits while minimizing risks.

Synergism of Docosahexaenoic Acid and Rosuvastatin in the Treatment of Donepezil Intolerant Alzheimer’s Disease Population- A Study with SH-SY5Y Cell Line

Background: Alzheimer’s disease (AD) has become a global concern. Many times the patients cannot tolerate the first line anti-Alzheimer’s drugs. This includes acetylcholinesterase inhibitors such as donepezil. This shifts the focus on repurposing study with drugs which are expected to alleviate AD. The purpose of the study was to evaluate the synergistic therapeutic potential of docosahexaenoic acid (DHA) and rosuvastatin combination against donepezil. Methods: RT-PCR was performed to find the effects of individual drugs and drug combination on caspase-3 (amyloid beta1-42 induced), IL-1β and TNF-α expression. Nitric oxide, lipid peroxide level and acetylcholinesterase activity were measured by spectrophotometric method. Results: DHA and rosuvastatin combination was better than donepezil in suppressing expressions of caspase-3 (2^ΔΔCT values for gene expression 0.21 Vs 0.60), IL-1β (2^ΔΔCT values for gene expression 0.13 Vs 0.28) and TNF-α (2^ΔΔCT values for gene expression 0.04 Vs 0.27). Similarly, DHA and rosuvastatin combination was better than donepezil in inhibiting nitric oxide level (73.96% Vs 66.19%). However, donepezil was better than DHA and rosuvastatin combination in suppressing lipid peroxide (72.40% Vs 67.20%) and acetylcholinesterase (91.85% Vs 82.33%). Conclusions: DHA and rosuvastatin combination was better than donepezil in suppressing most of the study parameters associated with AD. DHA and rosuvastatin combination was synergistic and may emerge as a substitute for donepezil to treat AD. The significance of the finding lies in the fact that the data generated in this research will open newer horizons in AD research. Once proven effective, the combination may be tried to manage mild to severe AD in donepezil intolerant AD population.

Patients with dementia: prevalence and type of drug-drug interactions.

Patients with Alzheimer's disease (AD) and other dementias are more frequently exposed to polymedication, mainly due to the presence of comorbidities, are particularly vulnerable to drug-related problems, and present greater risk of adverse effects due to drug-drug interactions (DDIs). To assess the prevalence of clinically relevant interactions in dementia patients using a routine database, we describe the most frequent interactions and risk factors associated with them to facilitate specific interventions and programs to prevent and minimize them. An observational, descriptive, and cross-sectional study that included patients with AD and other types of dementia (n = 100, 64% female) was conducted to identify potential DDI in their treatment using the Lexi-Interact/Lexicomp® database. A total of 769 drugs were prescribed, involving 190 different active ingredients; 83% of the treatments included five or more drugs. DDI occurred in 87% of the patients, of which 63.2% were female. A total of 689 DDIs were found, grouped in 448 drug pairs, with a mean of 6.9 ± 7.1 (range, 0-31) DDIs per patient, and 680 DDIs were considered clinically relevant. It was observed that 89.8% of the DDIs had a moderate level of severity, 23.5% had a good level of relevance, and pharmacodynamic-based DDIs accounted for 89.5%. The drugs most frequently involved in DDIs were quetiapine (24.5%) and acetylsalicylic acid (10%). A total of 97 DDIs were detected between the acetylcholinesterase inhibitors (AChEIs), and the remaining drugs were administered concomitantly. One of the most frequent DDIs was between AChEIs and beta-blocking agents (n = 29, 4.3%). The most important factors that showed the strongest association with the presence of drug interactions were the use of AChEIs (p = 0.01) and the total number of drugs (p = 0.014) taken by the patient. Patients with dementia present increased risk of DDIs. Among the most common drugs are psychotropic drugs, which are involved in pharmacodynamic interactions caused by the concomitant use of CNS-targeted drugs. The results highlight the difficulty to evaluate DDIs in clinical practice due to polymedication and variety of comorbidities. Therefore, it is important to review their treatment and consider metabolism inhibition or induction, and potentially P450 substrate overlapping.

Holistic exploration of silver nanoparticles synthesized from Carthamus oxycantha leaf extracts: Characterization and assessment of antioxidant, anti-α-amylase, and anti-cholinesterase activities using comprehensive statistical methods

In the burgeoning field of nanotechnology, plant-mediated nanoparticles (NPs) have attracted significant attention due to their small size, favorable chemical properties, and eco-friendly nature. We utilized Carthamus oxycantha leaf extract to synthesize silver nanoparticles (AgNPs) and evaluate their potential as antioxidants and inhibitors of acetylcholinesterase (AChE) and alpha-amylase (α-amylase). The AgNPs were characterized using advanced techniques. The UV–Vis spectrum recorded at 410 nm, with an absorbance of 2.3 a.u., confirmed the presence of AgNPs. Fourier transform infrared spectroscopy (FT-IR) indicated that functional groups from the extract were attached to the AgNP surface, aiding in their formation and stabilization. X-ray diffraction analysis (XRD) revealed four major peaks at 37, 43, 64, and 77, confirming AgNP synthesis. Scanning electron microscopy (SEM) showed that 80 % of the AgNPs were spherical, measuring 25–50 nm, while energy dispersive X-ray (EDX) analysis indicated that silver constituted 83 % of the material. The AgNPs demonstrated significant scavenging activity: 59.3 % with ABTS, 67.2 % with ammonium molybdate, 60.35 % with DPPH, 65.2 % with ferric chloride, and 55.2 % with H2O2. Both α-amylase and AChE were inhibited by AgNPs, exhibiting uncompetitive inhibition characteristics. For glucophage, Km decreased from 143 to 75 µg, and Vmax decreased from 45 % to 72 % as concentrations increased from 50 to 150 µg. The Km of AgNPs decreased from 25 to 17 µg, and Vmax decreased from 16 % to 37 %. The extract showed noncompetitive inhibition against α-amylase, while AgNPs caused noncompetitive inhibition in AChE. These findings highlight the potential of AgNPs as therapeutic agents for managing oxidative stress and enzyme-related disorders, paving the way for future research and applications in medicinal chemistry.

Evaluating the biological activity of rolB-transgenic Nicotiana tabacum plants using phytochemical and pharmacological approaches

The present study explored the impact of rolB gene transformation on biological activities of Nicotiana tabacum. PCR, and RT-qPCR were used to validate the integration of rolB gene and its expression. HPLC analysis was used for phytochemical profiling, and various in-vitro and in-vivo assays were used to assess pharmacological activities of wild-type and transgenic extracts using ANOVA and Tukey’s multiple comparison method for data analysis. Our findings indicated increased total phenolic content (24.4 ± 0.2 mg GAE/g DW of extract) and total flavonoid content (58.8 ± 1.1 mg QE/g DW of extract) in transgenic plants. In case of antioxidant activities, an increase in reducing power (51.82 ± 0.4 AAE mg/g), and radical scavenging (IC50 188 ± 2.7 µg/mL) was observed. Similarly, transgenic lines exhibited DNA protection against damage caused by free radicals. Moreover, we detected significant antileishmanial potential (IC50 350.7 ± 8.3 µg/mL), butyrylcholinesterase (IC50 268.6 ± 4.7 µg/mL), and acetylcholinesterase inhibitions (IC50 421.6 ± 3.7 µg/mL) in transgenic plants. Similarly, compared with the non-transgenic plants, the rolB-transgenic plants showed increased analgesic (71.4%), anti-inflammatory activities (77.8%), and 35.6% decrease in depression compared to non-transgenic plants. The improved pharmacological activities in transgenic plants have been linked to the level of phytochemicals that increase the therapeutic and curative properties of N. tabacum plants.

In Silico and ADMET Studies of Spiro-Quinazoline Compounds as Acetylcholine Esterase Inhibitors Against Alzheimer's Disease.

Alzheimer's disease (AD) is a prevalent neurodegenerative condition characterized by progressive cognitive decline and memory impairment resulting from the degeneration and death of brain neurons. Acetylcholinesterase (AChE) inhibitors are used in primary pharmacotherapy for numerous neurodegenerative conditions, providing their capacity to modulate acetylcholine levels crucial for cognitive function. Recently, quinazoline derivatives have emerged as a compelling model for neurodegenerative disease treatment, showcasing promising pharmacological features. Their unique structural features and pharmacokinetic profiles have sparked interest in their potential efficacy and safety across diverse neurodegenerative disorders. The exposure of quinazoline derivatives as a potential therapeutic way underscores the imperative for continued research exploration. Their multifaceted mechanisms of action and ability to target various pathways implicated in neurodegeneration offer exciting prospects for developing novel, effective, and well-tolerated treatments. Further investigations into their pharmacological activities and precise therapeutic roles are essential to advance our understanding of neurodegenerative disease pathophysiology and promote the development of modern therapeutic strategies to address this critical medical challenge. Quinazoline derivatives have gained eminent acetylcholinesterase (AChE) inhibitory activity. Their ability to effectively modulate AChE activity makes them promising candidates for treating neurological disorders, particularly Alzheimer's disease (AD). Their intricate molecular structures confer selectivity and affinity for AChE, offering potential for the development of novel therapeutic agents targeting cholinergic pathways. Hence, in this study, we designed, synthesized, and characterized a series of spiro[cycloalakane-1,2'-quinazoline derivatives (1-6) to assess their possible AChE inhibiting ability using docking into the active sites. The AChE inhibitory potential of spiro[cycloalkane-1,2'-quinazoline derivatives (1-6) was explored via docking studies of the AChE active site. The findings revealed significant inhibitory activity and highlighted the promising nature of these derivatives. The synthesized spiro[cycloalkane-1,2'-quinazoline derivatives (1-6) exhibited their notable potential as AChE inhibitors. The observed significant inhibitory activity suggested that these derivatives warrant further exploration as candidates for developing therapeutic agents in AChE inhibitory pathways. This study emphasizes the relevance of quinazoline derivatives in searching for novel treatments for neurological disorders, particularly associated with cholinergic dysfunction, and they could be a useful alternative therapeutic agent.

Theoretical examination of molecular docking, pharmacokinetics and in-silico design of specific tacrine derivatives as anti-Alzheimer agents

A common neurological illness that affects many individuals globally is Alzheimer's disease (AD). Its cause is currently unknown. One of the symptoms of AD is a reduction in cholinergic transmission, which has been linked to memory loss and cognitive impairment. Acetylcholinesterase (AChE) inhibitors such as donepezil, galantamine, and rivastigmine are used in medicine. However, their unfavourable side effects have caused them to be taken off the market. Because tacrine inhibits the enzyme AChE, molecular docking modelling has been used to simulate and create a variety of derivatives. The purpose of this work was to develop some strong Alzheimer's inhibitors and to calculate the binding scores of tacrine derivatives theoretically. Following docking, molecule A8 was selected as a template for creating new compounds since it had the greatest binding scores (-9.8 kcal/mol). The B3, B5, B6, B8, and B10 hypothetical molecules were constructed. The developed compounds' ADMET prediction and drug-likeness demonstrate strong pharmacokinetic properties. Furthermore, comparable strong inhibitor drugs against AD might be created using the in-silico methodologies used in this work.

Joint administration of sub-threshold doses of the acetylcholinesterase inhibitor donepezil with those of the NMDA receptor antagonist ketamine improved rats’ recognition memory abilities

Alzheimer’s Disease (AD) is a serious progressive neurodegenerative illness conducting to the decay of cognitive functions. A few drugs have been approved for the therapy of AD, including the acetylcholinesterase inhibitors (AChEIs) like donepezil. Their efficiency, however, is modest and their application is associated with toxicity. Recently, the N-methyl-D-aspartate (NMDA) receptor antagonist ketamine, a rapidly acting antidepressant, has been proposed as a potential agent for the treatment of AD. The present study was designed to investigate the effects exerted by the combination of sub-threshold doses of donepezil with those of ketamine on rats’ recognition memory abilities. For these experiments, the object recognition task (ORT) and the object location task (OLT), two procedures assessing non-spatial and spatial recognition memory respectively in rodents were used. Post-training acute administration of inactive doses of donepezil (0.3 mg/kg) and ketamine (1 mg/kg) counteracted non-spatial and spatial recognition memory impairments. The present findings, although preliminary, propose that the combined administration of ketamine and donepezil could represent a new strategy for the therapy of memory disorders, a common feature of AD patients.

Green synthesis, molecular docking and in vitro biological evaluation of novel hydrazones, pyrazoles, 1,2,4-triazoles and 1,3,4-oxadiazoles

Ultrasonic waves were used for synthesis of novel hydrazones, bishydrazones, pyrazoles, 1,2,4-triazole and 1,3,4-oxadiazole. The structural formulae of the synthesized compounds were elucidated in terms of elemental and spectroscopic analyses. All synthesized compounds were estimated by testing total antioxidant capacity, iron‐reducing power, the scavenging activity against ABTS and DPPH radicals in addition to testing anti‐diabetic, anti‐Alzheimer and anti‐arthritic activities. All compounds displayed good to potent bioactivity. Compounds 6, 10 exhibit the highest antioxidant and free radicals scavenging activities. Furthermore, compounds 6, 10 demonstrate the strongest inhibition of α‐amylase and α-glucosidase. Compound 12 exhibit strongest acetylcholinesterase inhibition among prepared compounds. However, compounds 18a,b, 19 show a significantly higher inhibition percentage for protein denaturation and proteinase. The most bioactive prepared compounds 6, 10 and 12 were investigated toward docking methodology against appropriate protein.

Alzheimer’s disease: newer modalities in treatment

Alzheimer’s disease (AD) remains insurmountable despite a long history of research and clinical development. It is projected to rise in the coming decades of public health due to the aging population worldwide. Understanding the basic tenets of the disease and targeting key steps remains a time-tested approach even for AD. Apart from the currently available treatment options namely NMDA blockers, and acetylcholinesterase inhibitors, recently monoclonal antibodies that target Aβ amyloid protein are approved. This review highlights the key features of currently approved drugs along with promising drugs in clinical development.

Inhibition Effects of Some Non-Proteinogenic Amino Acid Derivatives on Carbonic Anhydrase Isoenzymes and Acetylcholinesterase: An In Vitro Inhibition and Molecular Modeling Studies.

Amino acid derivatives are molecules of interest for medicinal chemistry and drug design studies due to their important chemical properties. In this study, the inhibition effects of some non-proteinogenic amino acid derivatives (hippuric acid (A), N-(9-Fluorenylmethoxycarbonyl)-D-valine (B), N-Z-(1-Benzotriazolylcarbonyl) methylamine (C), (S)-N-Z-1-Benzotriazolylcarbonyl-2-phenylethylamine (D)) on carbonic anhydrase I (hCA-I), II (hCA-II) isoenzymes and acetylcholinesterase (AChE) activity, whose inhibitors are of vital pharmacological importance, were examined. While carbonic anhydrase (CA) inhibitors are effective molecule candidates for the treatment of many diseases from glaucoma to cancer, acetylcholinesterase inhibitors are target molecules for the treatment of Alzheimer's disease. According to the results of this study, compound D had a strong inhibitory effect on hCA-I (IC50: 0.836 μM) and hCA-II (IC50: 0.661 μM), while compound B (IC50: 100 μM) showed a strong inhibitory effect on AChE activity. In addition, inhibition results were supported by molecular modeling studies. We hope that the obtained results will contribute to the synthesis of new and effective amino acid derivative inhibitors for CA and AChE.

Poly(3-hydroxybutyrate-co-3-hydroxyvalerate-co-3-hydroxyhexanoate)-based microspheres as a sustained platform for Huperzine A delivery for alzheimer's disease therapy

Huperzine A (HupA) is used in Alzheimer's disease (AD) therapy for its effective inhibition of acetylcholinesterase (AChE) and enhancement of cholinergic neuronal function. However, direct oral administration and injection of HupA cause side effects like nausea, anorexia, and rapid metabolism. Using a tripolymer, poly(3-hydroxybutyrate-co-3-hydroxyvalerate-co-3-hydroxyhexanoate (PBVHx), from the polyhydroxyalkanoate (PHA) family synthesized via synthetic biology, we present a novel AD therapy strategy with peritoneally administered PBVHx microspheres loaded with HupA (HupA-PBVHxMs). This approach extends HupA's metabolic duration in the blood and brain, enhancing AChE inhibition efficacy. Uniformly sized HupA-PBVHxMs, created using microfluidics and rotary evaporation, show up to 70.4 % drug encapsulation efficiency, sustained HupA release for 40 days, reduced neurotoxicity from Aβ25–35, and maintained in vivo HupA supply and AChE inhibition for over 20 days. In cognitive tests, HupA-PBVHxMs improved function in AD mice. Thus, PBVHx microspheres with slower HupA release and lower biotoxicity offer a superior platform for sustained AChE inhibitor release, outperforming commercial PLGA microspheres.

Halogenated monopyridinium oximes are less effective in reactivation of phosphylated cholinesterases than bisquaternary oximes

Mono-quaternary pyridinium oximes derived from K-oximes K027, K048 and K203 were designed, synthesized and evaluated for the reactivation of organophosphate-inhibited cholinesterases. The incorporation of the halogen atoms to the structure decreased the pKa value of the oxime group resulting in an increased formation of oximate necessary for reactivation. The stability and pKa values were found to be similar to analogous bis-quaternary compounds. Some mono-quaternary oximes resulted as relatively strong inhibitors of human acetylcholinesterase. Nevertheless, the reactivation ability of mono-quaternary oximes for organophosphate-inhibited cholinesterases was lower compared to their bis-quaternary analogues. These results were further confirmed by the determination of reactivation kinetics, when in some cases novel compounds showed improvement reactivation compared to the tested standards, but no improvement to bis-quaternary K-oximes. A computational study investigated reactivation process for K027, and its two analogues for VX-inhibited AChE. This study revealed slight differences between reactivation of mono-quaternary and bis-quaternary oximes.Abbreviations: 2-PAM, pralidoxime; AChE, acetylcholinesterase; ACN, acetonitrile; ATCI, acetylcholine iodide; BChE, butyrylcholinesterase; BTCI, butyrylcholine iodide; Bu3SnSnBu3, bis(tributyltin) Et2O, diethyl ether; ChEs, cholinesterases; CNS, central nervous system; DAD, diode array detector; DIBAL-H, diisobutylaluminium hydride; DMF, dimethylformamide; DMSO, dimethyl sulfoxide; DTNB, 5,5́-dithiobis-2-nitrobenzoic acid; Et3N, triethylamine; EtOAc, ethyl acetate; EWG, electron withdrawing group; HI-6, asoxime; hrAChE, human recombinant acetylcholinesterase; hrBChE, human recombinant butyrylcholinesterase; hrChEs, human recombinant cholinesterases; HPLC, high-performance liquid chromatography; HRMS, high-resolution mass spectrometry; KD, dissociation constant; kr, first-order reactivation rate constant; kr2, second-order reactivation rate constant; LüH-6, obidoxime; MeOH, methanol; MM, molecular mechanics; MMC-4, methoxime; m.p., melting point; NCIs, non-covalent interactions; NEDPA, 4-nitrophenyl ethyl dimethylphosphoramidate; NEMP, 4-nitrophenyl ethyl methylphosphonate; NIMP, isopropyl methylphosphonate; NMR, nuclear magnetic resonance spectroscopy; OPs, organophosphates; PBS, phosphate-buffered saline; Pd(dppf)Cl2.CH2Cl2, [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) in complex with dichloromethane; pKa, negative decimal logarithm of the dissociation constant; POX, paraoxon; PPh3, triphenylphosphine; QM, quantum mechanics; rt, room temperature; SN2, bimolecular nucleophilic substitution; SNAc, nucleophilic acyl substitution; THF, tetrahydrofuran; TMC-4, trimedoxime; TNB, 5-thio-2-nitrobenzoic acid; UHPLC, ultra high-performance liquid chromatography; UV, ultraviolet; UV–VIS, ultraviolet–visible.

Phytochemical screening and toxicity assessment of compounds isolated from the leaves of Mangifera indica L. for the control of Spodoptera litura (Lepidoptera; Noctuidae)

This study aimed to analyze the phytochemical composition and antioxidative capabilities of mango leaves (Mangifera indica L., Nam Dok Mai), indigenous to Sa Kaeo Province, Thailand. Various solvents with differing polarities, including n-hexane, DCM, ethyl acetate, and MeOH, were utilized for leaf extraction. The findings revealed the existence of eight groups of phytochemical compounds: alkaloids, flavonoids, coumarins, saponins, tannins, terpenoids, steroids, and cardiac glycosides. The MeOH crude extract exhibited the highest concentration of total phenolic compounds at 409.88 ±0.02 mg GAE/g. Furthermore, the MeOH crude extract demonstrated the strongest antioxidant activity, with an IC50 value of 0.52 ±0.02 μg/ml, as determined by the DPPH method. High-performance liquid chromatography (HPLC) was employed to identify gallic acid and mangiferin in the MeOH crude extract. Laboratory tests were conducted using the topical application method to evaluate the toxicity of the M. indica leaf crude extract on 2nd instar Spodoptera litura larvae. The MeOH crude extract exhibited high efficacy, with an LD50 value of 10.58 µg per larvae within 24 hours. Gallic acid and mangiferin were identified as the primary active ingredients, with LCD50 values of 1.19 µg per larvae and 1.90 µg per larvae, respectively, within 24 hours. Additionally, the impact on detoxification enzymes (24 hours post-treatment) was assessed in surviving 2nd instar S. litura larvae using the topical application method. The MeOH extract treatment resulted in 1.31-fold inhibition of carboxylesterase (CE), 1.31-fold inhibition of glutathione-S-transferase (GST), and 1.32-fold inhibition of acetylcholinesterase (AChE).

Novel Dual Acetyl- and Butyrylcholinesterase Inhibitors Based on the Pyridyl–Pyridazine Moiety for the Potential Treatment of Alzheimer’s Disease

Background: Alzheimer’s disease (AD) is characterized by cholinergic dysfunction, making the inhibition of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) critical for improving cholinergic neurotransmission. However, the development of effective dual inhibitors remains challenging. Objective: This study aims to synthesize and evaluate novel pyridazine-containing compounds as potential dual inhibitors of AChE and BuChE for AD treatment. Methods: Ten novel pyridazine-containing compounds were synthesized and characterized using IR, 1H NMR, and 13C NMR. The inhibitory activities against AChE and BuChE were assessed in vitro, and pharmacokinetic properties were explored through in silico ADME studies. Molecular dynamics simulations were performed for the most active compound. Results: Compound 5 was the most potent inhibitor, with IC50 values of 0.26 µM for AChE and 0.19 µM for BuChE, outperforming rivastigmine and tacrine, and showing competitive results with donepezil. Docking studies revealed a binding affinity of −10.21 kcal/mol to AChE and -13.84 kcal/mol to BuChE, with stable interactions confirmed by molecular dynamics simulations. In silico ADME studies identified favorable pharmacokinetic properties for compounds 5, 8, and 9, with Compound 5 showing the best activity. Conclusions: Compound 5 demonstrates strong potential as a dual cholinesterase inhibitor for Alzheimer’s disease, supported by both in vitro and in silico analyses. These findings provide a basis for further optimization and development of these novel inhibitors.

A Review of Muscle Relaxants in Anesthesia in Patients with Neuromuscular Disorders Including Guillain-Barré Syndrome, Myasthenia Gravis, Duchenne Muscular Dystrophy, Charcot-Marie-Tooth Disease, and Inflammatory Myopathies.

Anesthesia management in neuromuscular diseases (NMDs) is a complex challenge, requiring careful preoperative evaluation, tailored treatment strategies, and vigilant perioperative monitoring. This review examines the nuances of anesthesia in patients with NMD, addressing potential complications such as intubation difficulties, respiratory failure, and adverse effects of anesthetics and neuromuscular conduction blocking agents (NMBAs). Nondepolarizing NMBAs, including steroidal agents and benzylisoquinolines, are analyzed for their role, risks, and optimal use based on procedural requirements and patient characteristics. Challenges with depolarizing agents such as succinylcholine are highlighted, emphasizing the need for careful evaluation and monitoring to reduce the risk of adverse events such as malignant hyperthermia and hyperkalemia. The review highlights the role of reversal agents, particularly sugammadex, as a safer and more effective alternative to traditional acetylcholinesterase inhibitors such as neostigmine. Sugammadex reduces the risk of complications such as prolonged paralysis and respiratory failure in patients with NMD. In addition, anesthesia considerations tailored to specific NMDs, including Guillain-Barre syndrome, myasthenia gravis, Duchenne muscular dystrophy, Charcot-Marie-Tooth disease, and inflammatory myopathies are presented, including monitoring techniques and individualized approaches. Based on the available literature and the authors' clinical experience, this review aims to discuss the role of muscle relaxants in anesthesia in patients with the aforementioned neuromuscular disorders. This document uses the latest possible articles, covering items from 1992 to 2024.

Evaluation of the Enzyme Inhibition, Antioxidant, and Antimicrobial Activities of Apricots, Plums, and Their Hybrid Fruits

The current study focuses on evaluating the enzyme inhibition (acetylcholinesterase, α-amylase, α-glucosidase, pancreatin lipase), antioxidant, and antimicrobial activities of the “Modesto” apricot, “Stanley” plum, and their hybrid the “Stendesto” plum–apricot. The “Stendesto” is the only successful plum–apricot hybrid in Bulgaria. A spectrophotometric approach was used to evaluate the antioxidant activity following four complementary assays (DPPH, ABTS, FRAP, and CUPRAC). The “Stendesto” plum–apricot revealed its enhanced antioxidant potential compared to its parental lines. Apart from the free phenolics extraction, two other techniques (alkaline and acid hydrolysis) were applied to reveal the biological potential of the studied fruit. Not only free but also bound phenolic extracts were able to inhibit α-glucosidase and acetylcholinesterase, while none of the extracts inhibited lipase or α-amylase. None of the apricot extracts had antimicrobial activity, while the other fruit had limited antimicrobial activity. The proposed results undoubtedly reveal that hybrid fruits possess enhanced biological activity compared to their parents. This is a first comprehensive evaluation of hybrid fruits with reference to parental lines. This makes them an interesting research topic that should be better explored.